Nocturnal Hypoventilation in the Patients Submitted to Thoracic Surgery

Introduction Nocturnal hypoventilation may occur due to obesity, concomitant chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, and/or the use of narcotic analgesics. The aim of the study was to evaluate the risk and severity of nocturnal hypoventilation as assessed by transcutaneous continuous capnography in the patients submitted to thoracic surgery. Materials and Methods The material of the study consisted of 45 obese (BMI 34.8 ± 3.7 kg/m2) and 23 nonobese (25.5 ± 3.6 kg/m2) patients, who underwent thoracic surgery because of malignant (57 patients) and nonmalignant tumors. All the patients received routine analgesic treatment after surgery including intravenous morphine sulfate. Overnight transcutaneous measurements of CO2 partial pressure (tcpCO2) were performed before and after surgery in search of nocturnal hypoventilation, i.e., the periods lasting at least 10 minutes with tcpCO2 above 55 mmHg. Results Nocturnal hypoventilation during the first night after thoracic surgery was detected in 10 patients (15%), all obese, three of them with COPD, four with high suspicion of moderate-to-severe OSA syndrome, and one with chronic daytime hypercapnia. In the patients with nocturnal hypoventilation, the mean tcpCO2 was 53.4 ± 6.1 mmHg, maximal tcpCO2 was 59.9 ± 8.4 mmHg, and minimal tcpCO2 was 46.4 ± 6.7 mmHg during the first night after surgery. In these patients, there were higher values of minimal, mean, and maximal tcpCO2 in the preoperative period. Nocturnal hypoventilation in the postoperative period did not influence the duration of hospitalization. Among 12 patients with primary lung cancer who died during the first two years of observation, there were 11 patients without nocturnal hypoventilation in the early postoperative period. Conclusion Nocturnal hypoventilation may occur in the patients after thoracic surgery, especially in obese patients with bronchial obstruction, obstructive sleep apnea, or chronic daytime hypercapnia, and does not influence the duration of hospitalization.


Introduction
With increasing global epidemics of obesity [1,2] and the progress in thoracic surgical procedures [3], the probability of a need to perform surgical treatment of lung tumors in obese patients also increases. It has been suggested that the obese patients submitted to thoracic surgery should be distinguished as a special group of patients at the increased risk of perioperative complications [4]. Obesity itself carries a risk of occurrence of abnormalities in the breathing pattern, especially during sleep [5]. Sleep hypoventilation is one of the sleep-breathing disorders occurring in some of the obese persons [6].
Sleep hypoventilation as assessed by transcutaneous continuous measurement of carbon dioxide partial pressure (tcpCO 2 ) may be defned as an increase of tcpCO 2 to a value >55 mmHg for a period of at least 10 minutes or an increase of tcpCO 2 to a value >50 mmHg, but also exceeding by ≥10 mmHg awake values, for a period of at least 10 minutes [7].
In obese patients, sleep hypoventilation may occur even in the absence of diurnal hypercapnia [8]. It may be regarded as a sign preceding the development of chronic respiratory insufciency [8].
Beyond obesity, the other main causes of nocturnal hypoventilation include chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), neuromuscular disorders, and severe chest wall abnormalities [9,10]. In COPD patients, hypoventilation during sleep is a common feature, frst appearing during REM (rapid eye movement) sleep; then, in non-REM sleep, before daytime, chronic hypercapnia will develop [11]. OSA, although very common in the adult population, in majority of cases remains unrecognized and untreated [12]. In addition, OSA frequently co-occurs with obesity and, in minor degree, with COPD [10].
Sleep hypoventilation, causing nocturnal hypoxemia and hypercapnia, is not rarely severe [13] and may be aggravated by the suppression of central respiratory drive, such as occurring after opioid analgesics [14]. Opioids, in turn, are routinely ordered after thoracic surgical procedures [15]. On the other hand, postoperative pain has to be managed properly, and the doses of opioid use have to be sufcient in order to avoid sufering of the patient [16]. Up to 46% of patients may experience opioid-induced hypoventilation in the postoperative period [17]. Tis is particularly important as the patients with postoperative hypoventilation are at 2.5 times increased risk of rescue actions [17]. Tis might be important especially in the patients undergoing surgical procedures that diminish the area of respiratory gas exchange. Tus, the patients undergoing pulmonectomy, lobectomy, or anatomical wedge resection might be at risk of developing respiratory insufciency during sleep after thoracic surgery due to sleep hypoventilation.
Regardless of the cause of nocturnal hypoventilation during sleep, it may be associated with an increased risk of postoperative morbidity [18]. It has been found that the patients with hypoventilation during sleep might need increased caution and care during the postoperative period [19].
Te frequency of occurrence of nocturnal hypoventilation in the patients submitted to thoracic surgery has not been established yet. In addition, it is still unknown whether the nocturnal hypoventilation in the patients after thoracic surgery is associated with prolonged hospitalization or remote consequences.
Te aim of the study was to evaluate the risk of the occurrence of sleep hypoventilation as assessed by wholenight capnography, in the postoperative period in the surgically treated obese and nonobese patients with malignant and nonmalignant tumors of the lung, and to assess the twoyear survival in the lung cancer patients with and without sleep hypoventilation.
In all the patients, the analgesic treatment in the postoperative period included 1% morphine at a rate of 1-2 ml/h i.v., ketoprofen 100 mg i.v., every 12 hours, and metamizol 1 g i.v., every 6 hours.
Inclusion criterion was as follows: consecutive patients submitted to planned thoracic surgery who gave informed consent for nocturnal, whole-night capnography. Exclusion criteria encompassed patients under 18 years of age, patients who needed opioid treatment in the preoperative period, patients intolerant to ear-lobe sensor, and the patients with severe neuromuscular diseases or thoracic deformities.
Transcutaneous capnography (radiometer TCM4 TOSCA) was performed continuously from 10 p.m. to 6.00 a.m. during the night preceding thoracic surgery in all the patients and repeated during the frst night after the surgical procedure in 66 patients. Te registration was performed with an ear clip. Transcutaneous oxygen saturation (SpO 2 ) and tcpCO 2 were registered, and the following parameters were analyzed: minimal SpO 2 , maximal SpO 2 , mean SpO 2 , minimal tcpCO 2 , maximal tcpCO 2 , and mean tcpCO 2 . Nocturnal hypoventilation was defned according to American Academy of Sleep Medicine rules, as stated above [7].
Te probability of obstructive sleep apnea (OSA) was estimated retrospectively based on the STOP-Bang questionnaire [21] at the end of the follow-up period in all but one alive patient. Te score of at least 5 indicated a high risk of moderate-to-severe OSA.
For statistical analyses, program STATISTICA 12 (StatSoft Inc.) was used. Te normality of parameters was checked with the Kolmogorov-Smirnov test. Student's t-test was used for data comparison. Te level of signifcance of the diferences was established at p < 0.05.

Results
Nocturnal hypoventilation in the preoperative period was found in two patients (3%) and persisted in both of them in the postoperative period. Nocturnal hypoventilation in the postoperative period was detected in ten patients (fve women). Te patients with nocturnal hypoventilation in the postoperative period were all obese (BMI 35.0 ± 4.3 kg/m 2 ), three of them had COPD (with mild bronchial obstruction, stage 2) and one of them had daytime chronic hypercapnia in the preoperative period. Tere were three patients with lung cancer, three patients with lung metastases of renal (two patients) or rectal (one patient) cancers, and four patients with nonmalignant lung tumors.
Te patients with postoperative nocturnal hypoventilation as compared with the patients without nocturnal hypoventilation had higher BMI (p < 0.05), higher daytime preoperative PaCO 2 (p < 0.05), lower SpO 2 in the preoperative period (p < 0.05), higher values of the mean (p < 0.01), minimal (p < 0.001) and maximal (p < 0.0001) tcpCO 2 in the preoperative period, and higher values of the mean, minimal, and maximal tcpCO 2 (p < 0.0001) in the postoperative period; the duration of hospitalization was similar in both groups (Table 1).
Te diferences in the results of capnographic measurements a night before and a night after thoracic surgery are shown in Table 2. Tere was a signifcant increase in the minimal nocturnal tcpCO 2 and a signifcant decrease in the mean, minimal, and maximal nocturnal SaO 2 in the postoperative period as compared with the preoperative period ( Table 2).
Te mean follow-up of the patients was 26.5 ± 12 months. Te STOP-Bang questionnaire was applied to all but one alive patient at the end of follow-up. Te mean score in the STOP-Bang questionnaire was 3.5 ± 1.7 and the score ≥5 was obtained in 16 patients (31.4%), all but one obese. Among the patients with postoperative nocturnal hypoventilation, a high probability of moderate-to-severe OSA syndrome as assessed by the STOP-Bang questionnaire was found in four of them.
Twelve patients with primary lung cancer died during the time of observation, including 11 patients without nocturnal hypoventilation in the early postoperative period.

Discussion
Te results of this study with the use of transcutaneous capnography in the patients submitted to thoracic surgery revealed a risk of nocturnal hypoventilation during the frst night in the postoperative period in 15% of patients. Nocturnal hypoventilation in the postoperative period occurred exclusively in obese patients and was found in around 22% of the patients with a BMI > 30 kg/m 2 . Coexisting COPD or OSA syndrome also infuenced the occurrence of nocturnal hypoventilation in the postoperative period. Te results of the diurnal ABG studies did not allow us to predict nocturnal hypoventilation occurring in our patients, although the mean values of preoperative daytime PaCO 2 were higher in the patient with than in that without nocturnal hypoventilation in the postoperative period, and nocturnal hypoventilation was present in the only patient with chronic daytime hypercapnia in the preoperative period. Te differences between tcpCO 2 and the PaCO 2 obtained from the ABG studies are usually small and insignifcant [22] and may be accepted in almost all the patients with chronic diseases [23]. Tus, it can be admitted that the results of capnography obtained in our patients adequately mirrored respiratory gas exchange abnormalities. Sleep hypoventilation may occur in the patients with normal results of routinely performed daytime ABG studies [8], as in all but one of our patients. Diagnosing sleep hypoventilation is important, as this respiratory abnormality may precede daytime chronic and complete respiratory insufciency [11].
Sleep hypoventilation in obese persons may develop as a consequence of sleep-breathing disorders, including OSA syndrome [24,25]. Tus, our patients were asked the questions of the STOP-Bang questionnaire in order to estimate the probability of OSA syndrome, and in two patients with nocturnal hypoventilation, the results were positive.
Transcutaneous capnography in the surgical units was used more than 20 years ago in the pregnant patients during laparoscopic cholecystectomy [26]. In the patients after major colorectal surgery, transcutaneous capnography revealed a signifcant increase in mean values of tcpCO 2 measured in the postoperative period as compared with the preoperative period and an even more signifcant increase in patients receiving opioid analgesia than in the patients receiving epidural anesthesia [27]. In the obese patients undergoing bariatric surgery, the results of transcutaneous capnography showed better agreement with PaCO 2 than end-tidal capnography [28]. Capnography was successfully applied in the postanesthesia unit in order to evaluate its usefulness in monitoring surgically treated OSA patients [29]. Recently, it has been postulated to incorporate capnography and the STOP-Bang questionnaire [30] or capnography and nocturnal pulse oximetry [31] to the standard practice in the postanesthesia care units in order to reduce respiratory complications after surgical procedures.
In the whole group of our patients, there was a slight but signifcant decrease of oxygenation of the arterial blood and the increase of the minimal tcpCO 2 during postoperative night as compared with preoperative night. Tis could be a result of decreased lung volumes and continuous opioid administration in the early postoperative period. In the smaller group of patients with already established nocturnal hypercapnia, the changes of tcpCO 2 and SpO 2 were not signifcant. Tus, it can be assumed that the analgesic treatment with opioids in standard doses was associated with Canadian Respiratory Journal minimal risk of nocturnal hypoventilation, even in the obese patients. Tis statement has direct clinical implications, taking into account the decreased pain level in obese patients and thus the need of adequate analgesic treatment [32].
Opioids may induce hypoventilation and other respiratory abnormalities in several ways [33]. Opioids are associated not only with sleep-related hypoventilation but also with OSA [34]. In the patients in the postanesthesia care unit, there is a risk of sustained hypoventilation, which results in hypercapnia, induced by the opioids, as recently shown in the study measuring end-tidal CO 2 levels and minute ventilation [35]. Te other study, however, with the use of capnography in the postanesthesia care unit revealed a tendency to hypocapnia, which in contrary is a result of hyperventilation, and other respiratory abnormalities [36].
Te main limitations of the study encompassed the lack of preoperative polysomnography with the evaluation of neurophysiological sleep structure, especially with the possibility of diferentiation of REM and non-REM sleep phases, and the detection of sleep-breathing disorders, such as sleep apneas and hypopneas, as well as the lack of postoperative polysomnography. Te lack of  polysomnography and the ensuing lack of objective data in the presence of sleep-breathing disorders enabled the differentiation between overlap syndromes (COPD + OSA) with or without nocturnal hypoventilation. In addition, if capnography was performed during polysomnography, more information regarding the association of hypercapnia with sleep stages or sleep-breathing disorders could be obtained.
Te main strengths of the study are as follows: transcutaneous capnography was performed twice, in the preoperative and postoperative periods in the patients submitted to thoracic surgery; there was a long follow-up period; and the assessment of the coexisting possible sleepbreathing disorder, such as OSA, in the studied population of the patients was performed.

Conclusion
Nocturnal hypoventilation may occur in the patients after thoracic surgery, especially in obese patients with even mild bronchial obstruction, obstructive sleep apnea syndrome, or chronic daytime hypercapnia.

Data Availability
Te data that support the fndings of this study are available from the corresponding author upon reasonable request.

Ethical Approval
Te research was approved by the Bioethical Commission at Wroclaw Medical University.

Consent
All patients provided their written informed consent to participate in the study.

Disclosure
Te study was a part of research project number SUBZ.C110.22.064 at Wroclaw Medical University and research project number SUBZ.C110.23.061 at Wrocław Medical University, Poland.